Plymorphic forms of deferasirox (ICL670A)

ABSTRACT

The invention relates to crystalline forms of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and to its amorphous form, to processes for the preparation thereof, to compositions containing the same and their uses for the manufacture of a medicament for the treatment of the human body.

The invention relates to new crystalline forms of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid; theprocesses for preparation of these crystalline forms, compositionscontaining these crystalline forms, and the use of these crystallineforms in diagnostic methods or therapeutic treatment of warm-bloodedanimals, especially humans.

BACKGROUND OF THE INVENTION

The drug 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid isan orally active iron chelator that is indicated in the treatment ofiron overload in transfusion dependent anemias, in particularthalassemia major, thalassemia intermediate and in sickle cell diseaseto reduce iron-related morbidity and mortality.4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid can also beused in the treatment of hemochromatosis. In general, the preparation of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid is known inthe art. However, it is also known that different crystalline forms ofthe same drug may have substantial differences in certainpharmaceutically important properties. Therefore, there is a continuingneed for new solid forms of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and newmethods of preparation.

SUMMARY OF THE INVENTION

In accordance with one aspect, the invention provides a crystalline formA of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.Preferably, the crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid has anX-ray diffraction pattern with a peak at an angle of refraction 2 theta(θ) of 10.0°, 10.5°, 14.1°, 16.6°, 23.1°, 25.1°, 25.7°, 26.2°±0.2° asdepicted in FIG. 1. Preferably, the crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid has a Ramanspectrum with significant bands 3083, 1623, 1609, 1517, 1458, 1352, 991cm⁻¹±0.3 cm⁻¹ as depicted in FIG. 3.

In accordance with yet another aspect, the invention provides acomposition that contains4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in a solidform, wherein at least 80% by weight of the solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid is itscrystalline form A having an X-ray diffraction pattern with a peak at anangle of refraction 2 θ of 10.0°, 10.5°, 14.1°, 16.6°, 23.1°, 25.1°,25.7°, 26.2°±0.2° as depicted in FIG. 1. Various embodiments andvariants are provided.

In accordance with yet another aspect, the invention provides apharmaceutical composition that includes crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and apharmaceutically acceptable carrier or diluent. Preferably, thepharmaceutical composition is for oral administration.

In accordance with yet another aspect, the invention provides a processfor making the crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, theprocess including:

-   -   (a) providing a solution of        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid        e.g. in amorphous form, in either a protic or an aprotic        solvent;    -   (b) cooling the solution to form the crystalline form A of        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid;        and    -   (c) isolating the crystalline form A of        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.        Various embodiments and variants are provided.

In accordance with one aspect, the invention provides a crystalline formB of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.Preferably, the crystalline form B of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid has anX-ray diffraction pattern with a peak at an angle of refraction 2 theta(θ) of 6.5°, 7.4°, 10.8°, 13.4°, 14.8°, 19.2°, 21.7°, 26.1°±0.2° asdepicted in FIG. 4.

In accordance with yet another aspect, the invention provides acomposition that contains4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in a solidform, wherein at least 80% by weight of the solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid is itscrystalline form B having an X-ray diffraction pattern with a peak at anangle of refraction 2 θ of 6.5°, 7.4°, 10.8°, 13.4°, 14.8°, 19.2°,21.7°, 26.1°±0.2° as depicted in FIG. 4.

In accordance with yet another aspect, the invention provides apharmaceutical composition that includes crystalline form B of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and apharmaceutically acceptable carrier or diluent. Preferably, thepharmaceutical composition is for oral administration.

One aspect of the present invention relates to a process for making thecrystalline form B of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, theprocess including:

-   -   (a) heating the amorphous material above the glass transition        temperature, e.g. above 95° C., e.g. above 95° C. or until a        temperature equal to 105° C.,    -   (b) starting the crystallisation by further heating at a        temperature of, e.g. 150° C. until a temperature equal to about        190° C., e.g. equal to 190° C.,    -   (c) isolating the crystals of crystalline form B of        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

In a further embodiment the invention pertains to the amorphous form of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid andcompositions containing the amorphous form of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.Preferably, the amorphous form of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid has a Ramanspectrum with significant bands 3079, 1624, 1608, 1519, 1496, 1472,1460, 1362, 1316, 997, 991 cm⁻¹±3 cm⁻¹ as depicted in FIG. 7.Preferably, the amorphous form of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid shows onRAMAN spectroscopy bands at 1496, 1472, 1362, 1316 cm⁻¹±3 cm⁻¹

The invention pertains to a process for making the amorphous form of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, saidprocess comprises the following steps:

-   -   (a) heating, e.g. the crystalline form of modification A or        modification B, e.g. above its melting point of 261° C. for the        crystalline form of modification A,    -   (b) quenching to a temperature of about 20-25° C. or below        rapidly to obtain the amorphous form.

The invention also pertains to an alternative process for making theamorphous form of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, saidprocess comprises the following steps:

-   -   (a) dissolving the crystalline form of modification A or        modification B of        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in        a solvent, e.g. an aqueous solvent, e.g. water, or in a mixture        of 50% organic solvent/50% aqueous medium, e.g. 50% water/50%        methylbutylether, or 50% water/50% diethylether, or in a mixture        of organic solvents, e.g. 50% 3 pentanone/50% methylbutylether,        50%1-octanol/50% toluene, or 50% dioxane/50% toluene, or 50%        toluene/50% diisopropylether, or 50% n-hexane/50% acetonitrile    -   (b) fast evaporation of the solvent, e.g. under a stream of        nitrogen    -   (c) isolating the amorphous solid

The advantageous property of the amorphous form is its highestsolubility, e.g. as compared to the crystalline form A or B.

Another aspect of the invention relates to a crystalline form S_(A) of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.Preferably, the crystalline form S_(A) of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid has anX-ray diffraction pattern as depicted in FIG. 8.

In accordance with one aspect, the invention provides a crystalline formC of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.Preferably, the crystalline form C of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid has anX-ray diffraction pattern with a peak at an angle of refraction 2 theta(6) of 9.2°, 12.4°, 13.2°, 16.3°, 18.3°, 21.3°, 22.2°, 24.2°, 25.1°±0.2°as depicted in FIG. 9.

In accordance with another aspect, the invention provides a compositionthat contains 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoicacid in a solid form, wherein at least 80% by weight of the solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid is itscrystalline form C having an X-ray diffraction pattern with a peak at anangle of refraction 2 θ of 9.2°, 12.4°, 13.2°, 16.3°, 18.3°, 21.3°,22.2°, 24.2°, 25.1°±0.2° as depicted in FIG. 9. Various embodiments andvariants are provided.

In accordance with another aspect, the invention provides apharmaceutical composition that includes crystalline form C of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and apharmaceutically acceptable carrier or diluent. Preferably, thepharmaceutical composition is for oral administration.

In accordance with another aspect, the invention provides a process formaking the crystalline form C of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, theprocess including:

-   -   (a) 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid        is dissolved in THF/water/Ethanol, e.g. (2:4:4),    -   (b) solution of step (b) is allowed to dry, e.g. by flushing        with nitrogen at room temperature,    -   (c) the dry precipitate of step (d) is resuspended with either a        mixture V/V of a solvent 1, e.g. acetonitrile, methanol or        dichloromethane and of solvent 2, e.g. n-hexane, toluene or        cyclohexane,    -   (d) the suspension or solution of step (c) is agitated using        high-speed vortexer, e.g. at about 30° C., e.g. 30° C., e.g. for        about 2 hours, e.g. 2 hours,    -   (e) the solution of step (d) is evaporated, e.g. at room        temperature, e.g. under a stream of nitrogen.    -   (f) the modification C of step (f) is isolated.

In a further embodiment the invention pertains to the crystalline form Cof 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid andcompositions containing the crystalline form C of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.Preferably, the crystalline form C of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid has a Ramanspectrum with significant bands 3066(w, broad), 2973(w), 2940(w),1601(st), 1530(w), 1517(m), 1467(m), 1414(w), 1341(st), 1300(w),1264(w), 1167(w), 1042(w), 986(m), 837(w), 781(w), 659(w), 413(w) and166(w) cm⁻¹±3 cm⁻¹ as depicted in FIG. 10. Preferably, the crystallineform C of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acidshows on RAMAN spectroscopy bands at 1601 and 1341 cm⁻¹±3 cm⁻¹

In accordance with another aspect, the invention provides a crystallineform D of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.Preferably, the crystalline form D of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid has anX-ray diffraction pattern with a peak at an angle of refraction 2 theta(θ) of 7.0°, 9.4°, 10.6°, 11.3°, 13.9°, 15.0°, 20.4°, 21.4°±0.2° asdepicted in FIG. 11.

In accordance with another aspect, the invention provides a compositionthat contains 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoicacid in a solid form, wherein at least 80% by weight of the solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid is itscrystalline form D having an X-ray diffraction pattern with a peak at anangle of refraction 2 θ of 7.0°, 9.4°, 10.6°, 11.3°, 13.9°, 15.0°,20.4°, 21.4°±0.2° as depicted in FIG. 11.

In accordance with yet another aspect, the invention provides apharmaceutical composition that includes crystalline form D of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and apharmaceutically acceptable carrier or diluent. Preferably, thepharmaceutical composition is for oral administration.

One aspect of the present invention relates to a process for making thecrystalline form D of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, theprocess including:

-   -   (a) suspending the modification A material in a solvent, e.g. a        mixture of diethylamine/cyclohexane v/v (1/1),    -   (b) mixing the suspension of step (a), e.g. at 30° C. e.g. for 2        hours,    -   (c) filtering the mixture of step (b), e.g. on a 0.2 mm filter,        e.g. with regular cellulose membrane,    -   (d) evaporating the solution of step (c), e.g. under stream of        N₂,    -   (e) isolating the crystals of crystalline form D of        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

In a further embodiment the invention pertains to the crystalline form Dof 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid andcompositions containing the crystalline form D of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.Preferably, the form D of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid has a Ramanspectrum with significant bands 3071 (w, broad), 2973 (w, broad), 2940(w, broad), 2887 (w, broad), 2852 (w, broad), 1604 (st), 1521 (m), 1483(w, broad), 1462 (w, broad), 1385 (w, broad), 1346 (st), 1266 (w), 1158(w), 1137 (w), 1034 (w), 984 (w), 660 (w), 414 (w) and 115 (w) cm⁻¹ asdepicted in FIG. 12. Preferably, the crystalline form D of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid shows onRAMAN spectroscopy bands at 1521 and 1483 cm⁻¹±3 cm⁻¹.

Another aspect of the invention relates to a crystalline form S_(B) of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.Preferably, the crystalline form S_(B) of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid has anX-ray diffraction pattern as depicted in FIG. 13.

In accordance with one aspect, the invention provides a crystalline formS_(B) of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.Preferably, the crystalline form S_(B) of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid has anX-ray diffraction pattern with a peak at an angle of refraction 2 theta(6) of 9.4°, 10.0°, 11.3°, 12.8°, 15.0°, 16.1°, 22.1°, 24.3°±0.2° asdepicted in FIG. 13.

In accordance with yet another aspect, the invention provides acomposition that contains4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in a solidform, wherein at least 80% by weight of the solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid is itscrystalline form S_(B) having an X-ray diffraction pattern with a peakat an angle of refraction 2 θ of 9.4°, 10.0°, 11.3°, 12.8°, 15.0°,16.1°, 22.1°, 24.3°±0.2° as depicted in FIG. 13.

In accordance with yet another aspect, the invention provides apharmaceutical composition that includes crystalline form S_(B) of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and apharmaceutically acceptable carrier or diluent. Preferably, thepharmaceutical composition is for oral administration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the X-ray powder diffraction diagram of crystalline form Aof 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

FIG. 2 shows the DSC curve of crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

FIG. 3 shows the Raman spectrum crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

FIG. 4 shows the X-ray powder diffraction diagram of crystalline form Bof 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

FIG. 5 shows the DSC curve of crystalline form B of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

FIG. 6 shows the X-ray powder diffraction diagram of amorphous4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

FIG. 7 shows the Raman spectrum of amorphous4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

FIG. 8 shows the X-ray powder diffraction diagram of solvate form S_(A)4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

FIG. 9 shows the X-ray powder diffraction diagram of crystalline form Cof 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

FIG. 10 shows the Raman spectrum crystalline form C of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

FIG. 11 shows the X-ray powder diffraction diagram of crystalline form Dof 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

FIG. 12 shows the Raman spectrum crystalline form D of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

FIG. 13 shows the X-ray powder diffraction diagram of solvate form S_(B)4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methodsand materials are described.

For the purposes of the present invention, the following terms aredefined below. The crystalline compound, designated herein as“crystalline form A” and referred to hereinafter as crystalline form Aof 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, is anew crystalline polymorph of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid differentfrom known polymorphs. It is characterized via X-ray powder diffractionand DSC. It is further described below.

The crystalline compound, designated herein as “crystalline form B” andreferred to hereinafter as crystalline form B of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, is a newcrystalline polymorph of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid differentfrom known polymorphs. It is characterized via X-ray powder diffractionand DSC. It is further described below.

4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid can also bein the amorphous form.

For the purposes of the present invention, the following terms aredefined below.

The crystalline compound, designated herein as “crystalline form C” andreferred to hereinafter as crystalline form C of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, is a newcrystalline polymorph of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid differentfrom known polymorphs. It is characterized via X-ray powder diffraction.It is further described below.

The crystalline compound, designated herein as “crystalline form D” andreferred to hereinafter as crystalline form D of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, is a newcrystalline polymorph of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid differentfrom known polymorphs. It is characterized via X-ray powder diffraction.It is further described below.

The crystalline compound, designated herein as “crystalline form S_(B)”and referred to hereinafter as crystalline form S_(B) of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, is a newcrystalline polymorph of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid differentfrom known polymorphs. It is characterized via X-ray powder diffraction.It is further described below.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally non-toxic and is notbiologically undesirable and includes that which is acceptable forveterinary use and/or human pharmaceutical use.

The term “composition” includes, but is not limited to, a powder, asolution, a suspension, a gel, an ointment, an emulsion and/or mixturesthereof. The term composition is intended to encompass a productcontaining the specified ingredients in the specified amounts, as wellas any product, which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. A “composition”may contain a single compound or a mixture of compounds. A “compound” isa chemical substance that includes molecules of the same chemicalstructure.

The term “pharmaceutical composition” is intended to encompass a productcomprising the active ingredient(s), pharmaceutically acceptableexcipients that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing the active ingredient, additional activeingredient(s) and pharmaceutically acceptable excipients.

The term “excipient” means a component of a pharmaceutical product thatis not the active ingredient, such as filler, diluent and carrier. Theexcipients that are useful in preparing a pharmaceutical composition arepreferably generally safe, non-toxic and neither biologically norotherwise undesirable, and are acceptable for veterinary use, as well ashuman pharmaceutical use. “A pharmaceutically acceptable excipient”, asused in the specification and claims, includes both one and more thanone such excipient.

“Therapeutically effective amount” means the amount of a compound that,when administered for treating or preventing a disease, is sufficient toeffect such treatment or prevention for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the patientto be treated.

When referring to a chemical reaction, the terms “treating”,“contacting” and “reacting” are used interchangeably herein and refer toadding or mixing two or more reagents under appropriate conditions toproduce the indicated and/or desired product. It should be appreciatedthat the reaction which produces the indicated and/or desired productmay not necessarily result directly from the combination of two reagentswhich were initially added, i.e., there may be one or more intermediateswhich are produced in the mixture which ultimately leads to theformation of the indicated and/or desired product.

The term “substantially free of” in reference to a composition, as usedherein, means that the substance form which the composition is free ofcannot be detected by methods known to those skilled in the art.

The term “essentially pure” is understood in the context of the presentinvention to mean especially that at least 90%, preferably at least 95%by weight of the crystals of an acid addition salt of formula (I) arepresent in the crystal form according to the invention.

In the context with stating that, e.g. the A, B, C or D-crystal form of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid exhibits anX-ray diffraction diagram essentially as in FIG. 1, 4, 9 or 11respectively, the term “essentially” means that at least the major linesof the diagram depicted in FIG. 1, 4, 9 or 11 respectively, i.e. thosehaving a relative line intensity of more than 20%, especially more than30%, as compared to the most intense line in the diagram, have to bepresent.

In the context with stating that, e.g. the S_(A) or S_(B)-crystal formof 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid exhibitsan X-ray diffraction diagram essentially as in FIG. 8 or 13respectively, the term “essentially” means that at least the major linesof the diagram depicted in FIG. 8 or 13 respectively, i.e. those havinga relative line intensity of more than 20%, especially more than 30%, ascompared to the most intense line in the diagram, have to be present.

4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid has thefollowing chemical structure:

4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid isdescribed in example 5 of the granted EP 09114118, its manufacturingprocess is also described in EP 0914118.

The invention relates to a crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, to acrystalline form B of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, to acrystalline form C of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, to acrystalline form D of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, to asolvate form S_(A) of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, to asolvate form S_(B) of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and to anamorphous form of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

Different solid forms of the same drug may exhibit different properties,including characteristics that have functional implications with respectto their use as drug may have substantial differences in suchpharmaceutically important properties as dissolution rates andbioavailability. Likewise, different polymorphs may have differentprocessing properties, such as hydroscopisity, flowability and the like,which could affect their suitability as active pharmaceuticals forcommercial production.

X-ray powder diffraction patterns was measured on a Scintag X1 with CuKalpha radiation source, e.g. using a wavelength of 0.15406 nm. The X-raydiffraction pattern depicted in FIG. 1 is summarized in Table 1.

TABLE 1 Powder X-Ray Diffraction Peaks for the Form A CrystalModification of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoicacid ° deg 2θ d-space/Å Relative intensity 10.0 8.20 medium 10.5 8.45medium 14.1 6.32 medium 16.6 5.39 strong 23.1 3.93 medium 25.1 3.63medium 25.7 3.55 medium 26.2 3.49 low

It should be kept in mind that slight variations in observed 2θ anglesor d-spacing values are expected based on the specific diffractometeremployed, the analyst and the sample preparation technique. Morevariation is expected for the relative peak intensities.

Identification of the exact crystalline form of a compound should bebased primarily on observed 2 θ angles with lesser importance attributedto relative peak intensities. Some margin of error is present in each ofthe 26 angle assignments reported herein. The assigned margin of error,in a preferred variant, the crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid isapproximately ±0.2° for each of the peak assignments.

The crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid may be alsocharacterized by Differential Scanning calorimeter (DSC). Thecrystalline form A exhibits a characteristic pattern in DifferentialScanning calorimeter (DSC) analysis as depicted in FIG. 2. DSC analysiswas measured on a Perkin Elmer DSC7 at a heating rate of 10K/min. Thecrystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid has acharacteristic peak at about 261° C., e.g. at 261° C. Some margin oferror is present in each of the characteristic peak reported herein. Theassigned margin of error is approximately +/−2K, but can be larger, e.g.in particular lower if impurities are present.

One or more of physical properties and/or spectroscopic properties canbe the basis for characterizing the crystal or polymorphic forms of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

The invention also provides a composition containing solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, which isat least 80%, by total weight of the solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in thecomposition, its crystalline form A. The preferred form of thiscomposition is solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid powdersuitable for use as active ingredient in formulating pharmaceuticalproducts. The remainder of the solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in thecomposition, i.e., 20% or less of the total weight of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid may be,e.g., other crystalline forms of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid. In onespecific embodiment, the composition contains at least 90% of thecrystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid withrespect to the total weight of the solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in thecomposition. In another specific embodiment, the composition contains atleast 95% of the crystalline form A with respect to total weight of thesolid 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid inthe composition.

A process for the preparation of crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid is alsoprovided. The process involves:

-   -   (a) providing a solution        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in        either a protic or aprotic solvent, e.g. using the amorphous        form of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic        acid;    -   (b) cooling the solution to form crystalline form A of        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid;        and    -   (c) isolating the crystalline form A of        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

Non-limiting examples of the protic or aprotic solvents are thefollowing: THF (tetrahydrofuran)/Ethanol; Toluene/THF; Methanol/THF;Formic acid/ethanol; Water; HXF.

In one embodiment,4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid isdissolved in THF/Ethanol and heated to a temperature to obtain thecrystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid. Thisprocess is highly-reproducible and the resulting crystalline product hasgood filtration.

The above conditions on the selective preparation of the individualcrystal forms are not conclusive. In general, e.g., it is possible tovary parameters such as the weight ratio of the compound of formula (I)to the solvent and anti-solvent.

X-ray powder diffraction patterns was measured on a Scintag X1 with CuKalpha radiation source. The X-ray diffraction pattern depicted in FIG. 4is summarized in Table 2.

TABLE 2 Powder X-Ray Diffraction Peaks for the Form B CrystalModification of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoicacid ° deg 2θ d-space/Å Relative intensity 6.5 13.67 medium 7.4 11.93medium 10.8 8.16 strong 13.4 6.60 medium 14.8 5.97 medium 19.2 4.61 low21.7 4.08 medium 26.1 3.41 low

It should be kept in mind that slight variations in observed 2 θ anglesor d-spacing values are expected based on the specific diffractometeremployed, the analyst and the sample preparation technique. Morevariation is expected for the relative peak intensities. Identificationof the exact crystalline form of a compound should be based primarily onobserved 2 θ angles with lesser importance attributed to relative peakintensities.

Some margin of error is present in each of the 2 θ angle assignmentsreported herein. The assigned margin of error, in a preferred variant,the crystalline form B of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid isapproximately ±0.2° for each of the peak assignments.

The crystalline form B of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid may be alsocharacterized by Differential Scanning calorimeter (DSC). Thecrystalline form B exhibits a characteristic pattern in DifferentialScanning calorimeter (DSC) analysis as depicted in FIG. 4. DSC analysiswas measured on a Perkin Elmer DSC7. The crystalline form B of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid has acharacteristic peak at 226° C. Some margin of error is present in eachof the characteristic peak reported herein. The assigned margin of erroris +/−2K, but can be larger, e.g. in particular lower if purities arepresent.

One or more of physical properties and/or spectroscopic properties canbe the basis for characterizing the crystal or polymorphic forms of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

The invention also provides a composition containing solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, which isat least 80%, by total weight of the solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in thecomposition, its crystalline form B. The preferred form of thiscomposition is solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid powdersuitable for use as active ingredient in formulating pharmaceuticalproducts. The remainder of the solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in thecomposition, i.e., 20% or less of the total weight of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid may be,e.g., other crystalline forms of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid. In onespecific embodiment, the composition contains at least 90% of thecrystalline form B of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid withrespect to the total weight of the solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in thecomposition. In another specific embodiment, the composition contains atleast 95% of the crystalline form B with respect to total weight of thesolid 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid inthe composition.

A process for the preparation of crystalline form B of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid involvesthe following steps:

-   -   (a) heating the crystalline form A of        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid to        above its melting point of about 261° C.,    -   (b) cooling the melt of        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic of        step (a) to about room temperature or below to obtain the        amorphous form,    -   (c) recrystallization of the amorphous form of        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl] into        crystalline form B upon heating to a temperature above 95° C.,        preferably to above 190° C.,    -   (d) crystalline form B of        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl] can be isolated        by cooling to room temperature.

This process is highly-reproducible and the resulting crystallineproduct has good filtration.

A process for the preparation of the amorphous form of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid comprisesthe following steps:

-   -   (a) dissolving the crystalline form of modification A or        modification B of        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in        a solvent, e.g. an aqueous solvent, e.g. water, or in a mixture        of 50% organic solvent/50% aqueous medium, e.g. 50% water/50%        methylbutylether, or 50% water/50% diethylether, or in a mixture        of organic solvents, e.g. 50% toluene/50% acetonitrile, 50%        n-hexane/50% toluene, or or 50% n-hexane/50% acetonitrile    -   (b) fast evaporation of the solvent, e.g. under a stream of        nitrogen    -   (c) isolating the amorphous solid.

The above conditions on the selective preparation of the individualcrystal forms and the amorphous form are not conclusive. In general,e.g., it is possible to vary parameters such as the weight ratio of thecompound of formula (I) to the solvent.

The preferred form of this composition is solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid powdersuitable for use as an active ingredient in formulating pharmaceuticalproducts. The reminder of the solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in thecomposition, i.e., 20% or less of the total weight of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid may be,e.g., crystalline forms of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

Also provided are pharmaceutical compositions containing a crystallineform A of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acidand a pharmaceutically acceptable carrier.

Also provided are pharmaceutical compositions containing a crystallineform B of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acidand a pharmaceutically acceptable carrier.

The invention provides a composition comprising solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in itscrystalline form C or D or S_(B), or C and D, or C and/or D and S_(B).

The invention provides a composition containing4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, which isat least 80%, by total weight of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in thecomposition, its crystalline form C or D. The preferred form of thiscomposition is solid4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid powdersuitable for use as active ingredient in formulating pharmaceuticalproducts. The remainder of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in thecomposition, i.e., 20% or less of the total weight of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid may be,e.g., other crystalline forms of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid. In onespecific embodiment, the composition contains at least 90% of thecrystalline form C or D of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid withrespect to the total weight of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in thecomposition. In another specific embodiment, the composition contains atleast 95% of the crystalline form C or D with respect to total weight of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in thecomposition.

A process for the preparation of crystalline form C of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid is alsoprovided. The process involves:

-   -   (a) providing a solution        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in        a mixture of protic and/or aprotic solvents, e.g. in        THF/water/ethanol, e.g. (2:4:4), e.g. using the amorphous form        of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid;    -   (b) drying the solution of step (a),    -   (c) suspending the dry precipitate obtained in step (b), e.g. in        a mixture of solvents, e.g. a mixture comprising v/v of a        solvent 1, e.g. acetonitrile, methanol, or dichloromethane, and        of a solvent 2, e.g. n-hexane, toluene, or cyclohexane, e.g.        under agitation, e.g. using a high-speed vortexer, e.g. at about        30, e.g. at 30 e.g. for about 2 hours, e.g. for 2 hours,    -   (d) isolating the crystalline form C of        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid,        e.g. by evaporating the solution of step (c), e.g. at room        temperature, e.g. under a stream of nitrogen.

In one embodiment,4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid isdissolved in THF/ethanol, precipitated by addition of seeding crystalsof the crystalline form C of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid andaddition of ethanol as the anti-solvent, and crystalline form C of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid isobtained.

X-ray powder diffraction patterns was measured on a Bruker D8 GaddsDiffractometer, with CuK alpha radiation source, e.g. using a wavelengthof 0.15406 nm. The X-ray diffraction pattern depicted in FIG. 9 issummarized in Table 3.

TABLE 3 Powder X-Ray Diffraction Peaks for the Form C CrystalModification of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoicacid Relative intensity ° deg 2θ d-space (%) 9.2 9.577 Weak (32) 12.47.145 Strong (88) 13.2 6.719 Strong (85) 16.3 5.422 Strong (100) 18.34.836 Medium (58) 21.3 4.165 Medium (58) 22.2 4.002 Medium (64) 24.23.679 Medium (42) 25.1 3.539 Strong (84)

X-ray powder diffraction patterns was measured on a Bruker D8 GaddsDiffractometer, with CuK alpha radiation source, e.g. using a wavelengthof 0.15406 nm. The X-ray diffraction pattern depicted in FIG. 11 issummarized in Table 4.

TABLE 4 Powder X-Ray Diffraction Peaks for the Form C CrystalModification of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoicacid Relative intensity ° deg 2θ d-space (%) 7.0 12.656 Medium (52) 9.49.450 Medium (67) 10.6 8.353 Medium (49) 11.3 7.793 Medium (69) 13.96.369 Medium (44) 15.0 5.902 Strong (87) 20.4 4.355 Medium (72) 21.44.156 Strong (100)

X-ray powder diffraction patterns was measured on a Bruker D8 GaddsDiffractometer, with CuK alpha radiation source, e.g. using a wavelengthof 0.15406 nm. The X-ray diffraction pattern depicted in FIG. 13 issummarized in Table 5.

TABLE 5 Powder X-Ray Diffraction Peaks for the Form S_(B) CrystalModification of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoicacid Relative intensity ° deg 2θ d-space (%) 9.4 9.356 23 10.0 8.810 4011.3 7.846 100 12.8 6.903 23 15.0 5.894 70 16.1 5.489 33 22.1 4.021 3824.3 3.660 44

It should be kept in mind that slight variations in observed 26 anglesor d-spacing values are expected based on the specific diffractometeremployed, the analyst and the sample preparation technique. Morevariation is expected for the relative peak intensities. Identificationof the exact crystalline form of a compound should be based primarily onobserved 2 θ angles with lesser importance attributed to relative peakintensities.

Some margin of error is present in each of the 2 θ angle assignmentsreported herein. The assigned margin of error, in a preferred variant,the crystalline forms C, D and S_(B) of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid isapproximately ±0.2° for each of the peak assignments.

One or more of physical properties and/or spectroscopic properties canbe the basis for characterizing the crystal or polymorphic forms of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

A process for the preparation of crystalline form D of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid involvesthe following steps:

-   -   (a) suspending the modification A material in a solvent, e.g. a        mixture of diethylamine/cyclohexane v/v (1/1),    -   (b) mixing the suspension of step (a), e.g. at 30° C. e.g. for 2        hours,    -   (c) filtering the mixture of step (b), e.g. on a 0.2 mm filter,        e.g. with regular cellulose membrane,    -   (d) evaporating the solution of step (c), e.g. under stream of        N₂,    -   (e) isolating the crystals of crystalline form D of        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid.

A process for the preparation of the crystalline form S_(B) of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid comprisesthe following steps:

-   -   (a) suspending the crystalline form of modification A of        4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid in        a solvent, e.g. in DMF,    -   (b) the suspension of step (a) is sonicated, e.g. for about 15        min, e.g. for 15 min, and filtered, e.g. on 0.2 um regular        cellular membrane,    -   (c) solution of step (b) is added to water,    -   (d) the precipitate obtained in step (c) is filtered and dried,        e.g. under N2,    -   (e) the crystalline form S_(B) is isolated.

The above conditions on the selective preparation of the individualcrystal forms and the amorphous form are not conclusive. In general,e.g., it is possible to vary parameters such as the weight ratio of thecompound of formula (I) to the solvent.

Also provided are pharmaceutical compositions containing a crystallineform C of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acidand a pharmaceutically acceptable carrier.

Also provided are pharmaceutical compositions containing a crystallineform D of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acidand a pharmaceutically acceptable carrier.

In addition to the active compound, the pharmaceutical compositioninclude one or more pharmaceutically acceptable carriers, also known asexcipients, which ordinarily lack pharmaceutical activity, but havevarious useful properties which may, e.g., enhance the stability,sterility, bioavailability and ease of formulation of a pharmaceuticalcomposition. These carriers are pharmaceutically acceptable, meaningthat they are not harmful to humans or animals when taken appropriatelyand are compatible with other ingredients in a given formulation. Thecarriers may be solid, semi-solid or liquid, and may be formulated withthe compound in bulk, but ultimately in the form of a unit-doseformulation, i.e., a physically discrete until containing a specificamount of active ingredient, such as a tablet or capsule. Thepharmaceutical compositions may include, in addition to a compound ofthis invention, one or more active pharmaceutical compounds.

The pharmaceutical compositions may be in the form of suspensions,solutions, elixirs, aerosols or solid dosage forms.

The pharmaceutical compositions are contemplated in various formulationssuitable for various modes of administration including, but not limitedto, inhalation, oral, rectal, parenteral (including subcutaneous,intradermal, intramuscular and intravenous), implantable and transdermaladministration. The most suitable route of administration in an givencase depends on the duration of the subject's condition, the length oftreatment desired, the nature and severity of the condition beingtreated, and the particular formulation that is being used. Theformulations may be in bulk or in unit dosage form, and may be preparedby methods well-known in the art for a given formulation.

The amount of active ingredient included in a unit dosage form dependson the type of formulation in which the active ingredient is presented.A pharmaceutical composition will generally contain about 0.1% by weightto about 99% by weight of the active ingredient, preferably about 1% byweight to 50% by weight for oral administration and about 0.2% by weightto about 20% by weight for parenteral administration.

Formulations suitable for oral administration include capsules (hard andsoft), cachets, lozenges, syrups, suppositories and tablets, eachcontaining a predetermined amount of the active compound; as a powder orgranules, as a solution or a suspension in an aqueous or non-aqueousliquid; or as an oil-in-water or water-in-oil emulsion. Suchformulations may be prepared by any suitable method of pharmacy thatincludes the step of bringing into association the active compound and asuitable carrier or carriers.

Oral administration is the preferred route of administration of thepresent invention.

In another aspect, the invention also provides methods of treatmentusing the compounds and the pharmaceutical compositions of thisinvention.

The compounds and compositions of this invention may be administered toa subject in an amount effective to be used for the treatment of anexcess of iron in the human or animal body and/or disorders related toexcess of iron in such subjects.

The present invention relates especially to crystalline form A andcrystalline form B and crystalline form C and crystalline form D of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid disclosedherein for the treatment of one of the said disorders or in thepreparation of a pharmacological agent for the treatment thereof.Various disorders of warm-blooded animals are linked with an excess ofmetals, in particular trivalent metals, in the body tissues. For examplealuminium in dialysis encephalopathy and osteomalacia, as well as inAlzheimer's disease. In other illnesses, in particular of man, an excessof iron occurs in the various tissues. This is designated as ironoverload (formerly haemosiderosis). It occurs, for example, afterparenteral administration of iron (especially repeated bloodtransfusions) or after increased uptake of iron from thegastrointestinal tract. Repeated transfusions are necessary in seriousanaemias, especially in thalassaemia major, the severe form ofβ-thalassaemia, but also in other anaemias. Increased iron absorptionfrom the gastrointestinal tract either takes place primarily, e.g. onaccount of a genetic defect (so-called haemochromatosis), orsecondarily, such as after anaemias in which blood transfusions are notnecessary, for example thalassaemia intermedia, a milder form ofβ-thalassaemia. A reduction in the iron(III) concentration is also ofinterest for the treatment of disorders due to iron(III)-dependentmicroorganisms and parasites, which is of key importance not only inhuman medicine, such as in particular in malaria, but also in veterinarymedicine. Complexing of other metals, in particular trivalent metals,can also be used for excretion thereof from the organism.

The invention relates also to a process for the treatment ofwarm-blooded animals suffering from said disorders wherein a quantity ofthe crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and/orcrystalline form B of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and/orcrystalline form C of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and/orcrystalline form D of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, which iseffective against the disease concerned is administered to warm-bloodedanimals in need of such treatment.

The invention relates moreover to the use of the crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and/orcrystalline form B of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and/orcrystalline form C of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and/orcrystalline form D of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid for thetreatment of an excess of iron in the human or animal body and/or adisorder related to the excess of iron, or for the preparation ofpharmaceutical compositions for use in treating the human or animalbody, especially in disorders related to the excess of iron.

The dosage of the active ingredient can depend on various factors, suchas activity and duration of action of the active ingredient, severity ofthe illness to be treated or its symptoms, manner of administration,warm-blooded animal species, sex, age, weight and/or individualcondition of the warm-blooded animal. The doses to be administered dailyin the case of oral administration are between 10 and approximately 120mg/kg, in particular 20 and approximately 80 mg/kg, and for awarm-blooded animal having a body weight of approximately 40 kg,preferably between approximately 400 mg and approximately 4,800 mg, inparticular approximately 800 mg to 3,200 mg, which is expedientlydivided into 2 to 12 individual doses.

The invention relates also to pharmaceutical preparations which comprisean effective amount, especially an effective amount for prevention ortreatment of one of the said diseases, especially a disorder related tothe excess of iron, of the crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and/orcrystalline form B of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and/orcrystalline form C of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and/orcrystalline form D of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, togetherwith pharmaceutically acceptable carriers which are suitable fortopical; enteral, e.g. oral or rectal; or parenteral administration andmay be inorganic or organic and solid or liquid.

Pharmaceutical preparations for enteral or parenteral administrationare, for example, those in unit dose forms, such as sugar-coatedtablets, tablets, dispersible tablets, effervescent tablets, capsules,suspendable powders, suspensions or suppositories, or ampoules. Theseare prepared in a manner known per se, e.g. by means of conventionalpan-coating, mixing, granulation or lyophilization processes.Pharmaceutical preparations for oral administration can thus be obtainedby combining the active ingredient with solid carriers, if desiredgranulating a mixture obtained and processing the mixture or granules,if desired or necessary, after addition of suitable adjuncts to givetablets or sugar-coated tablet cores.

Suitable carriers are, in particular, fillers such as sugars, e.g.lactose, sucrose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphates, e.g. tricalcium phosphate or calcium hydrogenphosphate, furthermore binders, such as starch pastes, using, forexample, maize, wheat, rice or potato starch, gelatin, tragacanth,methylcellulose and/or polyvinylpyrrolidone, and, if desired,disintegrants, such as the abovementioned starches, furthermorecarboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginicacid or a salt thereof, such as sodium alginate. Adjuncts are primarilyflow-regulating and lubricating agents, e.g. salicylic acid, talc,stearic acid or salts thereof, such as magnesium or calcium stearate,and/or polyethylene glycol. Sugar-coated tablet cores are provided withsuitable, if desired enteric, coatings, using, inter alia, concentratedsugar solutions which, if desired, contain gum arabic, talc,polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide,coating solutions in suitable organic solvents or solvent mixtures or,for the preparation of enteric coatings, solutions of suitable cellulosepreparations, such as acetylcellulose phthalate orhydroxypropylmethylcellulose phthalate. Colorants or pigments, e.g. forthe identification or the marking of various doses of active ingredient,can be added to the tablets or sugar-coated tablet coatings.

Dispersible tablets are tablets which rapidly disintegrate in acomparatively small amount of liquid, e.g. water, and which, if desired,contain flavourings or substances for masking the taste of the activeingredient. They can advantageously be employed for the oraladministration of large individual doses, in which the amount of activeingredient to be administered is so large that on administration as atablet which is to be swallowed in undivided form or without chewingthat it can no longer be conveniently ingested, in particular bychildren. Further orally administrable pharmaceutical preparations arehard gelatin capsules and also soft, closed capsules of gelatin and aplasticizer, such as glycerol or sorbitol. The hard gelatin capsules cancontain the active ingredient in the form of granules, e.g. as a mixturewith fillers, such as lactose, binders, such as starches, and/orglidants, such as talc or magnesium stearate, and, if desired,stabilizers. In soft capsules, the active ingredient is preferablydissolved or suspended in suitable liquids, such as fatty oils, liquidparaffin or liquid polyethylene glycols, it also being possible to addstabilizers.

Moreover, suspendable powders, e.g. those which are described as “powderin bottle”, abbreviated “PIB”, or ready-to-drink suspensions, aresuitable for an oral administration form. For this form, the activeingredient is mixed, for example, with pharmaceutically acceptablesurface-active substances, for example, sodium lauryl sulfate orpolysorbate, suspending auxiliaries, e.g. hydroxypropylcellulose,hydroxypropylmethylcellulose or another known from the prior art andpreviously described, for example, in “Handbook of PharmaceuticalExcipients”, pH regulators, such as citric or tartaric acid and theirsalts or a USP buffer and, if desired, fillers, e.g. lactose, andfurther auxiliaries, and dispensed into suitable vessels, advantageouslysingle-dose bottles or ampoules. Immediately before use, a specificamount of water is added and the suspension is prepared by shaking.Alternatively, the water can also be added even before dispensing.

Rectally administrable pharmaceutical preparations are, for example,suppositories which consist of a combination of the active ingredientwith a suppository base. A suitable suppository base is, for example,natural or synthetic triglycerides, paraffin hydrocarbons, polyethyleneglycols or higher alkanols. Gelatin rectal capsules can also be usedwhich contain a combination of the active ingredient with a basesubstance. Possible base substances are, for example, liquidtriglycerides, polyethylene glycols or paraffin hydrocarbons.

For parenteral administration, aqueous solutions of an active ingredientin water-soluble form, e.g. of a water-soluble salt, are primarilysuitable; furthermore suspensions of the active ingredient, such asappropriate oily injection suspensions, suitable lipophilic solvents orvehicles, such as fatty oils, e.g. sesame oil, or synthetic fatty acidesters, e.g. ethyl oleate or triglycerides, being used, or aqueousinjection suspensions which contain viscosity-increasing substances,e.g. sodium carboxymethylcellulose, sorbitol and/or dextran, and, ifdesired, also stabilizers.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of the compound and thecompositions of the present invention, as well as their utility. It willbe apparent to those skilled in the art, that many modifications, bothto materials, and methods, may be practiced with out departing from thepurpose and interest of this invention. The examples that follow are notintended to limit the scope of the invention as defined hereinabove oras claimed below.

EXAMPLES Example 1 Preparation of crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid usingTHF/ethanol and HXF Example 2 Preparation of crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid usingtoluene and THF Example 3 Preparation of crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid usingMethanol/THF Example 4 Preparation of crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid usingformic acid and ethanol Example 5 Preparation of crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid usingmethanol/THF and water Example 6 Preparation of crystalline form A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid usingmethanol/THF and HXF Example 7 Preparation of crystalline form B of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid fromrecrystallization of the amorphous form at temperature above 100° C.Example 8 Preparation of crystalline form B of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid fromrecrystallization of the amorphous form at temperature above 140° C.Example 9 Preparation of crystalline form C

4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid isdissolved in THF/water/Ethanol, e.g. (2:4:4). Said solution is dispensedinto a 96-well block to have a total amount of drug substance of 2 mgper well. The solution is then allowed to dry by flushing with nitrogenat room temperature. The dry precipitate is resuspended with either amixture of 125 microL of a solvent 1, e.g. acetonitrile, methanol ordichloromethane and 125 microL of solvent 2, e.g. n-hexane, toluene orcyclohexane. The suspension or solution is agitated using high-speedvortexer, e.g. at about 30° C., e.g. 30° C., e.g. for about 2 hours,e.g. 2 hours. The solution is evaporated, e.g. at room temperature, e.g.under a stream of nitrogen. The Modification C is isolated.

Example 10 Preparation of Crystalline Form D

About 50 mg of the modification A of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid aresuspended in 5 ml of a mixture of diethylamine/cyclohexane v/v (1/1).The suspension is then mixed 2 hours at 30° C. and filtrated on a 0.2 μmfilter with regular cellulose membrane. Then the solution is allowed toevaporate under stream of N₂. The solid precipitate is isolated andanalyzed by XRPD using a Bruker D8 Gadds Diffractometer.

What is claimed is:
 1. A crystalline form of4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid which showsan X-ray diffraction diagram of the type shown in FIG. 9, in which therelative peak intensities of each peak do not deviate by more than 10%from the relative peak intensities in the diagram shown in FIG. 9.